1, 2-dihydro-1-polyhydroxyalkyl-2-quinoxalinones



United States Patent OfiFice 3,366,628 Patented Jan. 30, 1968 This invention relates to new and useful 1,2-dihydro-1- polyhydroxyalkyl-2-quinoxalinones having pharmacological activity.

The novel compounds which are included within the scope of this invention are represented by the following wherein R is polyhydroxyalkyl, such as, D-ribityl, D-sorbityl, L-arabityl, L-rhamnityl, D-dulcityl, dihydroxy (lower)alkyl and trihydroxy(lower)alkyl; R is selected from the group consisting of lower alkyl, phenyl, nitrophenyl, lower alkylphenyl, halophenyl, lower alkoxyphenyl, benzyl, pyridyl, furyl and thienyl; R and R are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R and R when taken separately are selected from the group consisting of hydrogen, halogen, trifluoromethyl, lower alkyl and lower alkoxy and when R, and R are concatenated they form a methylene chain of three to four carbon atoms. Examples of such compounds include: 1,2-dihydro-3- [2-hydroxy-2- 2-furyl) vinyl] 1 (D-ribityl) 2 quinoxalinone; 1 (L arabityl) 1,2 dihydro 3 (2 hydroxypropenyl) 6,7- trimethylene 2 quinoxalinone; 1 (L arabityl) 1,2- dihydro 3 (2 hydroxypropenyl) 6,7 tetramethylene- 2-quinoxalinone and 1,2-dihydro-3-[2-hydroxy-2-(4-chlo rophenyl)vinyl] 6,7 dimethyl 1 (L rhamnityl) 2- quinoxalinone.

A process for synthesizing the compounds of the present invention is hereinafter described so as to enable a person skilled in the art of chemistry to prepare them. The process is schematically illustrated as follows:

I /OR R NHR1 O Condensation 6; R4 NHE I O OHiOORi a N R5 \*O Ri CH=C-R2 I \N/ Ra wherein R R R R R and R are defined as above and R is lower alkyl. The reaction is effected by admixing with stirring a 1,2-diamino compound, such as an :aminoaniline, an aminotetrahydronaphthaline or an aminoindane, with an a-ketocarboxylic acid ester, in an acidic aqueous media at steam bath temperatures for a period of from about one-half hour to three hours.

After the reaction is complete, the product is separated tion for water soluble products and filtration for those that precipitate. The 1,2-dihydro-l-polyhydroxyalkyl-2- quinoxalinones of the present invention may then be purified by recrystallization from a suitable solvent e.g. water-alkanol mixtures, alkanols and dimethylformamide.

Many of the reactants employed in the process of this invention are known compounds which are available from commercial sources, while the remainder can be prepared in accordance with standard organic procedures well known to those skilled in the art. In accord with the present invention the new 1,2-dihydro-l-polyhydroxyalkyl-Z- quinoxalinones herein described have been found to by standard recovery procedures, for example evaporapossess interesting pharmaceutical properties which render them useful as synthetic medicinals. More particularly, these compounds, in standard pharmacological tests have exhibited utility as anti-inflammatory agents.

When the compounds of this invention are employed as anti-inflammatory agents, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. They may be administered intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered parenterally at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in the range of from about 20 mg. to about 1000 mg. per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 50 mg. to about 700 mg. per day is most desirably employed in order to achieve effective results.

The following examples are given by way of illustration and are not to be construed as limitations of this invention, variations of which are possible without departing from the scope and spirit thereof.

Example I A solution of 2.0 g. (6.5 mmoles) of 2-amino-4,5'-dimethyl-N-(D-ribityl)-aniline monohydrochloride, 1.17 g. (6.5 mmoles) of sodium salt of ethyl acetopyruvate in 25 ml. of water and 1.0 ml. of acetic acid is warmed on a steambath (89 C.) for one and a half hours. Thereafter the mixture is cooled and the solvent is removed by evaporation leaving a yellow residue which is crystallized from methanol-water (9: 1) to yield 500 mg. (21%) of crude product, M.P. 2162l8 C.

3.05, 6.00 and 6.20,

Example II A mixture of 1.5 g. of 2-aminoN-(D-ribityl)-aniline and 1.2 g. of ethyl-Z-furoylpyruvate in 20 ml. of Water and 0.8 ml. of acetic acid is heated on a steambath for one hour. Thereafter, the reaction mixture is cooled and evaporated. The residue is crystallized from an ethanolwater mixture to yield 1,2 dihydro-3[2-hydroxy-2-(2- furyl) vinyl] 1- (D-ribityl) -2-quinoxalinone.

Example III A mixture of 1.0 g. of 2-amino-4,5-dichloro-N-(D- sorbityl)-aniline monohydrochloride and 1.0 g. of the potassium salt of ethyl acetopyruvate in 15 ml. of water and 0.5 ml. of acetic acid is heated on a steam bath for tWo hours. Thereafter, the reaction mixture is cooled and evaporated. The residue is crystallized from methanol- Water to yield 6,7-dichloro-1,2-dihydro-3-(2-hydroxypropenyl) -l-(D-sorbityl) -2-quinoxalinone.

Repeating the aforesaid procedure with the appropriate starting compounds, the following quinoxalinones are produced:

8 bromo 6 t butyl-l,2-dihydro-3-(2-hydroxypropenyl) l- (D-sorbityl) -2-quinoxalinone;

1,2 dihydro 3 (Z-hydroxypropenyl)-5,8-dimethoxyl-(D-sorbityl)-2-quinoxalinone;

7 bromo 1,2 dihydro 3-(2-hydroxybutenyl)-8- methyl-1(D-sorhityl) -2-quinoxalinone;

1,2 dihydro 3 (2 hydroxyhexenyl)-7-propoxy-1- (D-sor'oityl)-2-quinoxalinone; and

6 butyl 1,2 dihydro 3 (2-hydroxpyropenyl)-1- (D-sorbityl) -2-quinoxalinone.

Example IV A mixture of 8.3 g. of -arnino-6-(L-arabitylamino)- indane monohydrochloride and 4.3 g. of the sodium salt of methyl acetopyruvate in 100 ml. of water and 4 ml. of acetic acid is heated on a steambath for forty-five minutes. Thereafter, the reaction mixture is cooled, evaporated and the residue is crystallized from methanol to yield 1 (L arabityl) 1,2 dihydro-3-(2-hydroxypropenyl) -6,7-trimethylene-Z-quinoxalinone.

Example V A mixture of 8.7 g. of 2-amino-3(L-arabitylamino)- 5,6,7,8-tetrahydro naphthaline monohydrochloride and 5.1 g. of the potassium salt of ethyl acetopyruvate in 100 ml. of water and 4 ml. of acetic acid is heated on a steambath for one hour. Thereafter, the reaction mixture is cooled and evaporated. The residue is crystallized from methanol-water to yield 1 (L arabityl)-1,2-dihydro-3- (Z-hydroxypropenyl) -6,7tetramethylene-2-quinoxalinone.

Example VI Repeating the procedure of Example I! and V to react an appropriate aminoindane or aminotetrahydronaphthaline with an a-ketocarboxylic acid ester the following quinoxalinones are obtained:

1 (L arabityl) 1,2 dihydro-3-(2-hydroxybutenyl)- 6,7-trimethylene-Z-quinoxalinone;

1,2 dihydro 3 (2-hydroxy-2-phenylvinyl)-6,7-trimethylene-l- (D-ribityl) -2-quinoxalinone;

1,2 dihydro 3 [2 hydroxy-Z-(4-tolyl)vinyl]-6,7- tetramethylene-l-(D-sorbitol)-2-quinoxalinone;

1,2 dihydro 3 [2-hydroxy-2-(3-ethylphenyl)vinyl]- 6,7-tetramethylene-1-(L-rhamnityl) -2-quinoxalinone;

1 (D dulcityl) 1,2 dihydro 3-[2-hydroxy-2-(4- chlorophenyl vinyl] -6,7-trimethylene-Z-quinoxalinone;

1,2 dihydro 3 [2 hydroxy-2-(p-methoxyphenyl) vinyl] 1 (2,3 dihydroxy-l-propyl)-6,7-tetramethylene-Z-quinoxalinone;

1,2 dihydro 3 [2 hydroxy-3-phenylpropenyl)-1- (2,4 dihydroxy 1 butyl) 6,7-trimethylene-2-quinoxalinone; and

1 (L arabityl) 1,2 dihydro-3-[2-hydroxy-2 (4-nitrophenyl) vinyl] -6,7-tetr amethylene-2-quinoxalinone.

4- Example VII A mixture of 2.8 g. of 2-amino 4,5-bis-(trifiuorornethyD-N-(D-ribityD-aniline and 1.6 g. of ethyl isonicotinoyl-pyruvate in 25 ml. of water and 1.0 ml. of acetic acid is heated on a steam bath for one and a half hours. Thereafter, the reaction mixture is cooled and evaporated. The residue is crystallized from methanol-water to yield 6,7 bis (trifluoromethyl 1,2 dihydro 3 [2-hydroxy--2- (4-pyridyl) vinyl] -l- (D-ribityl -2-quinoxalinone.

Similarly, 1,2 dihydro 3 [Z-hydroxy 2 (2-pyridyl)vinyl] 1 (D-ribityl) 2 quinoxalinone; 1,2- dihydro 3 [2 hydroxy 2 (3-pyridyl)vinyl]-6,8- dimethyl l (D-ribityl) 2 quinoxalinone and 6,7-dimethoxy 1,2 dihydro 3 [2-hydroxy 2 (2-pyridyl) vinyl] -1- (D-ribityl -2-quinoxalinone are synthesized.

Example VIII A mixture of 5.0 g. of 2 amino 4,6-dimethyl-N- (L-arabityD-aniline and 4.0 g. of ethyl nicotinoylpyruvate in 60 ml. of water and 2.5 ml. of acetic acid is heated on a steambath for three hours. Thereafter, the reaction mixture is cooled and evaporated. The residue is crystallized from propanol-water to yield 1-(L-arabity1)-1,2- dihydro 3 [2-hydroxy 2 (3-pyridyl)vinyl]-6,8-dimethyl-Z-quinoxalinone.

Example IX A mixture of 5.1 g. of N-(2,3 dihydroxy 1 propyl) o-phenylenediamine dihydrochloride, 8.6 g. of the sodium salt of ethyl-Z-thenoylpyruvate in ml. of water and 10 ml. of acetic acid is refluxed for fifteen minutes. The resulting precipitate is then filtered and recrystallized from N,N-dirnethylformamide to yield 1,2 dihydro-l- (2,3 dihydroxy 1 propyl) 3 [2-hydroxy-2-(2- thienyl)vinyl]-2-quinoxalinone.

Similarly, the following compounds are synthesized:

1,2 dihydro 1 (3,4-dihydroxy 1 butyl)-3[2-hy droxy-Z-(2-thienyl)vinyl]-7-iodo-2-quinoxalinone;

5,8 diethoxy 1,2 dihydro 1 (2,3-dihydroxy-1- propyl) 3 [2-hydroxy 2 (2 thienyl)vinyl]-2 quinoxalinone; and

1,2 dihydro 3 [2 hydroxy 2 (4-ethoxyphenyl) vinyl] 1 (2,3 dihydroxy 1 propyl)-8-propyl-2- quinoxalinone.

Example X A mixture of 20.8 g. of 2 amino 4,5 dimethyl-N- (L-rharnnityl)-aniline monohydrochloride and 18.0 g. of the sodium salt of ethyl p-chlorobenzoylpyruvate in 250 ml. of water and 10 ml. of acetic acid is heated on a steambath for one hour. Thereafter, the reaction mixture is cooled and evaporated. The residue is crystallized from methanol to yield 1,2 dihydro-3-[2-hydroxy-2-(4- chlorophenyl)vinyl] 6,7 dimethyl l-(L-rhamnityD-Z- quinoxalinone.

When 2 amino-4-butyl-N-(Lrhamnityl)-aniline is reacted with ethyl p-bromobenzoylpyruvate, in the above manner, the product is 6 butyl 1,2 dihydro 3 [2- hydroxy-2-(4-bromophenyl)vinyl] 1 (L-rhamnityl) 2- quinoxalinone.

Example XI A mixture of 10.0 g. of Z-amino 4,5 dichloro-N-(D- dulcity1)-aniline monohydrochloride and 4.8 g. of the sodium salt of ethyl acetopyruvate in m1. of water and 5 ml. of acetic acid is heated on a steambath for three hours. Thereafter, the reaction mixture is cooled, evaporated and the residue is crystallized from ethanol to yield 6,7 dichloro 1 (D-dulcityl) -1,2 dihydro 3-(2- hydroxypropenyl -2-quinoxalinone.

In a similar manner, the following compounds are pro duced:

l-(D-dulcityl) 1,2 dihydro 3 [2 hydroxy-2-(3- iodophenyl) vinyl] -7-t-butyl-2-quinoxalinone;

l-(D-dulcityl) 7 iodo 1,2 dihydro 3-[2-hydroxy- 2- (4-propylphenyl)viny11-2-quinoxalinone; and

5 I-(D-dulcityl) 7 fiuoro 1,2 dihydro 3 (2-hydroxybutenyl)-2-quinoxalinone.

What is claimed is: 1. A compound selected from the group consisting of those having the formula:

wherein R is polyhydroxyalkyl; R is selected from the group consisting of lower alkyl phenyl, nitrophenyl, lower alkylphenyl, halophenyl, lower alkoxyphenyl, ben- Zyl, pyridyl, furyl and thienyl; R and R are both selected from the group consisting of hydrogen, bromo, lower alkyl and lower alkoXy; R and R when taken separately are selected from the group consisting of hydrogen, halogen, trifluoromethyl, lower alkyl and lower alkoxy and when R and R are concatenated they form a methylene chain of three to four carbon atoms.

2. A compound as described in claim 1 which is: 1,2- dihydro 3 (Z-hydroxypropenyl) 6,7 dimethyl-l-(D- ribityl)-2-quinoxalinone.

3. A compound as described in claim 1 which is: 1,2- dihydro 3 [Z-hydroxy 2 (2-fu1'yl)vinyl] 1 (D- ribityl) -2-quinox alinone.

4. A compound as described in claim 1 which is: 6,7- dichloro 1,2 dihydro 3 (2-hydroxypropenyl)-1-(D- sorbityl)-2-quinoxalinone.

5. A compound as described in claim 1 which is: l-(L- arabityl) 1,2 dihydro 3 (Z-hydroxypropenyl)-6,7-tri methylene-2-quinoxalinone.

6. A compound as described in claim 1 which is: 6,7- bis(trifiuoromethyl) 1,2 dihydro 3 [Z-hydroxy 2- (4-pyridyl) vinyl] 1- (D ribityl) -2-quinoxalinone.

7. A compound as described in claim 1 which is: l- (L-arabityl) 1,2 dihydro 3 [2-hydroXy-2-(3-pyridyl) vinyl]-6,8-dimethyl-2-quinoxalinone.

8. A compound as described in claim 1 which is: 1,2- dihydro 1 (2,3-dihydroxy 1 propyl) 3 [2-hydroxy-Z- Z-thienyl vinyl] -2-quinoxalinone.

9. A compound as described in claim 1 which is: 1,2- dihydro 3 [Z-hydnoxy 2-(4-chlorophenyl)vinyl]-6,7- dimethyl- 1- (L-rhamnityl -2-quinoxalinone.

10. A compound as described in claim 1 which is: 6,7- dichloro 1 (D-dulcityl) 1,2 dihydro 3 (2-hydroxypropenyl)-2-quinoxalinone.

References Cited UNITED STATES PATENTS 3,002,974 10/1961 Peten'ng 260250 LEWIS GOTTS, Primary Examiner. J. R. BROWN. Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULA:
 2. A COMPOUND AS DESCRIBED IN CLAIM 1 WHICH IS: 1,2DIHYDRO-3-(2HYDROXYPROPENYL)-6,7-DIMETHYL-1-(DRIBITYL)-2-QUINOXALINONE. 